* As is the custom, this document of the Pontifical Academy for Life
is published under the editorship of the President and Vice-President.

In drafting its contents, the Academy received input from an
international work group with specific expertise in the various
disciplines connected with xenotransplantation; this work group met many
times in the Vatican earlier this year.

Members of the work group are the following:

- Bishop Elio SgrecciaVice-President of the Pontifical Academy for LifeChairman

Prof. Marialuisa Lavitrano(xenotransplantation, biotechnologies, molecular biology and
genetics)Coordinator of "Italy Xenotransplant Project"
Member of Working Group on Xenotransplantation Council of Europe
Department of Experimental Medicine and Pathology
University "La Sapienza" - Rome, ITALY

- Msgr. Tullio PoliSecretariate of State (Sect. for Relations with States) VATICAN CITY

- Dr.Maria Isabel Telleria TapiaSecretariate of State (Sect. for Relations with States) VATICAN CITY

INTRODUCTION

Transplantation represents a highly successful means of treating a
variety of human illnesses. However, the number of transplants performed
is limited by a shortage of human organs and tissues1.
Xenotransplantation, the transplantation of organs, tissues or cells
from one species to another, if applied to man, would offer the
possibility of a huge supply of organs, tissues and cells for
transplantation thereby relieving the "chronic" shortage of
human donors. However, before xenotransplantation becomes a clinical
reality, there are practical challenges that must be overcome. One is
rejection, the process by which the body of the transplant recipient
attempts to rid itself of the transplant. Another is to ensure the
correct functioning, across species barriers, of the transplant in its
new host. Also, there is the need to minimize the likelihood of the
introduction of new infectious agents into the human population via the
transplant.

In addition there are concerns about xenotransplantation that require
theological, anthropological, psychological and ethical considerations,
as well as an examination of legal issues and procedural matters.

FIRST PART

SCIENTIFIC ASPECTS

HISTORICAL BACKGROUND

1. To date, there is only very limited experience in transplanting
xenogenic organsor tissues to humans. The attempts made in the
1960s and early 1970S used immunosuppressive therapies on the recipient
to prolongsurvival of the organ. The most striking success was
the nine-month survival of a chimpanzee kidney transplanted into a human
by REEMTSMA and colleagues2. In the 1980s, a baboon
heart was transplanted to a baby (Baby Fae) that survived briefly3;
however, rejection occurred within a few weeks. In the 1990s, baboon
livers were transplanted in two patients by STARZL and colleagues4.
Those patients survived for 70 days in one case and 26 days in the
other. The first patient was placed on an oral diet on the fifth
post-transplant day and spent most of his time in a regular ward,
leaving the hospital briefly on one occasion5. However, in
one of the two cases, a baboon pathogen (cytomegalovirus) was
apparently transferred to the patient, even though this did not result
in a disease process6. However, in both patients there was
evidence of an adequately functioning liver mass, sufficient to sustain
life. The baboon livers led to the presence of baboon proteins
synthesized by the liver; in some cases those proteins assumed the blood
levels that are characteristic of the baboon and not of the human.
Possible molecular incompatibility of those proteins poses a potential
problem of functionality for humans.

Transplants have also been attempted using pig hearts (three cases)
or livers (one case); in no case did the recipient survive more than 24
hours7.

While non-human primates have been preferred in the past as source
organs for humans, at present the scientific community and the
regulatory agencies in those countries which are addressing the issue
have ruled out the use of such source animals both because of the
increased risk of transmission of infection and because of a variety of
other ethical and practical concerns8. As a consequence many
researchers have settled on the use of pigs as a potential source
animals for xenotransplantation9. The use of genetic
engineering has resulted in significant improvement in survival time for
a pig organ in a non-human primate receiving immunosuppression10.
However, the survival time of such organs does not yet approach that of
human organs transplanted to other humans (allotransplantation).
Therefore, certain barriers to xenotransplantation remain11.

Further genetic engineering of source animals and/or use of
additional/new immunosuppressive agents are the two approaches that are
considered most likely to prolong the survival of a xenotransplant12.
Clearly more research in xenotransplantation is needed and should be
done.

CURRENT SITUATION

Rejection: Immunology of Organ Xenografting

2. There are four immunological barriers that must be overcome for
achieving successful organ xenotransplantation from pig to primate
(human and non-human). First, hyperacute rejection, which is
caused by xenoreactive natural antibodies and complement of the
recipient acting against endothelial cells of the source animal organ.
Second, acute vascular rejection caused by the combined effect of
elicited xenoreactive antibodies and activated host natural killer cells
and monocytes. In combination these stimuli (the anti-graft antibodies
and the activated host cells) result in activation of the endothelial
cells of the source organ. Endothelial cell activation leads to general
inflammation with resultant thrombosis (platelet aggregation and
activation of the coagulation cascade) resulting in organ rejection.
Third, the xenograft counterpart of classical T cell mediated
rejection of allografts (transplantation between individuals of the
same species) will almost certainly occur. Finally, xenografts may also
be subject to chronic rejection in a manner analogous to
allografts.

Hyperacute Rejection. Recipient xenoreactive natural antibodies
and complement are the two major factors that result in hyperacute
rejection of an immediately-vascularized organ. Pre-existing
xenoreactive natural antibodies bind with vascular endothelial cells of
the pig organ13. These antibodies are directed primarily
towards a sugar moiety, the Gal-α
(1,3)-Gal-β
(1,4)-GlcNac antigens of the pig, also known as "
α-gal"14. The bound antibodies fix and
activate complement, with the combination of antibodies and activated
complement leading to endothelial activation which result in thrombosis,
rapid graft ischemia and rejection. Elimination of xenoreactive natural
antibodies provides one method to overcome hyperacute rejection15.
Hyperacute rejection has also been overcome by methods that inhibit
complement16.

Among the different approaches for achieving inhibition of
complement, the one that has proven most effective is based on invitro experiments in which a human protein that inhibits human
complement activation is introduced into the membrane of pig endothelial
cells. The molecule first tested was human Decay Accelerating Factor,
or hDAF. The presence of hDAF in thepig endothelial cells
prevented lysis of those cells and would thus, presumably, prevent the
activation of the cells17. These findings suggested that the
production of transgenic pigs expressing hDAF might provide an approach
for overcoming hyperacute rejection of pig organs transplanted into
primates. Certain research groups have produced such transgenic pigs and
have demonstrated that organs from these pigs usually do not undergo
hyperacute rejection18. Based on these results with
transgenic hDAF-expressing pigs, it appears that hvperacute rejection
can be overcome, which is the first major triumph of gene therapy in the
field of organ transplantation.

Another possible solution to hyperacute rejection is to eliminate, or
greatly reduce the expression of "α-gal"
from pigs by knocking out the 1,3 galactosyl transferase gene, which is
needed for the expression of "α-gal"19.
This has not yet been accomplished in pigs, although present-day cloning
technology could make this possible.

Acute Vascular Rejection. Acute Vascular Rejection is
precipitated by elicited xenoreactive antibodies and by the possible
infiltration of host inflammatory cells, monocytes and natural killer
cells, that invade the xenograft20. Endothelial cells are
activated resulting in thrombosis, compromised blood flow and rejection21.
Acute vascular rejection now represents the principle immunological
barrier to successful xenotransplantation. Studies of acute vascular
rejection in animals has shown that the use of immunosuppression leads
to organ survival for a far greater length of time than is seen in
untreated cases22. An alternative approach for overcoming
acute vascular rejection is further genetic engineering animals/organ23.
A number of genes that may suppress the inflammatory response that
appears to cause acute vascular rejection are now being studied.

T Cell Response. If acute vascular rejection can be overcome, it
is expected that there will be a xenograft counterpart of the allogeneic
T cell rejection response24. There are disagreements whether
the xenogenic T cell response will be more difficult to overcome than
the allogeneic one, which today is easily controlled. In addition to the
use of immunosuppression, there is the possibility that in
pig-to-primatetransplantswe might achieve tolerance (non-reactivity
of the immune system of the recipient to pig antigens without
immunosuppression)25. Such tolerance is the hope of
transplantation in general and may be aided in the xenogenic arena by
further genetic engineering of the source animal.

Chronic Xenograft Rejection. There is evidence that—as with
allotransplants, —even when a transplant survives all the above
rejection phases, there is the possibility that it will be rejected
months or years later26. This is referred to as
"chronic" rejection. The main pathology of chronic graft
failure involves smooth muscle cell proliferation and obliteration of
the lumens of blood vessels.

Experimental Models

3. Xenotransplantation of organs has been studied primarily in small
animal models and in pig-to-nonhuman-primate combinations.

Small animal models. The principal model used involves
transplantation of hamster or mouse hearts to rats. For the most part,
the rejection of a hamster heart by a rat is similar to the rejection of
a mouse heart. However, the rat does not have sufficient preformed
xenoreactive natural antibodies to reject a mouse or hamster heart
hyperacutely; thus rejection is dependent on the synthesis of anti-graft
antibodies that, together with recipient complement, lead to rejection
of the organ27. Transplantation of mouse or hamster hearts to
rats is therefore thought to be a good model of acute vascular
rejection. The preliminary findings that have emerged from small animal
transplants are the following: administration of immunosuppression to
the rat can lead to long-term survival of hamster hearts28.
In this sense, rejection of a hamster organ transplanted to a rat appear
to differ from acute vascular rejection of a pig organ in a non-human
primate in which hyperacute rejection has been overcome. In the
pig-to-nonhuman-primate model, immunosuppression alone is currently
unable to lead to long-term survival. The second finding in the hamster
or mouse heart transplants to rats has been the achievement of
"accommodation"29. Accommodation refers to the
survival of an organ in the presence of anti-graft antibodies and
complement. Short-term inhibition of complement coupled with continuing
inhibition of T cells leads to long-term survival in these two
situations. An interesting finding regarding accommodation is that the
surviving organ expresses genes in its endothelium and smooth muscle
cells that protect the organ from rejection30. To what extent
these protective genes can be used therapeutically to aid pig organ
survival in primates is not clear. Isolated cases of accommodation have
been described in human allogeneic transplants as well31.

Large animal models. The principal model today remains transgenic
pigs expressing hDAF32 and, in some cases, other human genes
inhibiting complement cascade, coupled with immunosuppression in order
to achieve survival. In most cases, normal pig organs are rejected
hyperacutely by nonhuman primates, and thus, more rapidly than
transgenic pig organs expressing hDAF33. Even when hyperacute
rejection is avoided, the hDAF transgenic organs are rejected in
nonhuman primates by a process that mimics acute vascular rejection,
although rejection can be very much delayed34. Transgenic pig
hearts have been shown to survive for up to 99 days when they are not
asked to do life-supporting work (heterotopic transplant)35.When placed in the position of having to support life (orthotopic
transplant),the longest survival periods have been a month
for a cardiac xenograft36 and 78 days for a renal xenograft37;
most organs are rejected in a shorter period of time. Scientists propose
two different approaches, which can be combined for achieving longer
survival periods of pig organs in primates. The first is to try
different immunosuppressive protocols, and the second is to produce pigs
that express additional transgenes that might inhibit rejection factors
associated with acute vascular rejection.

Xenozoonoses: the transmission of infectious agents from one species
to another

4. Over sixty porcine infectious agents with a potential to cause
disease in humans have been identified38. Development of
"clean" lines of source animals, with a certified health
status, is under way39. Control measures include the birth of
pigs by hysterotomy (caesarean derived), carefully controlled
environments and routine monitoring of pigs and their handlers.
These steps appear to have excluded almost all known infectious agents
of concern. However, it cannot be ruled out that an unknown porcine
virus might exist which causes no pathology in pigs but which may cause
disease in humans.

As is true for all other mammalian species, pigs have sequences in
their DNA that encode retroviruses (PERV—Porcine Endogenous
RetroViruses)40. Weiss and colleagues showed that
pig retroviruses could infect human cells in vitro41.
There are no satisfactory animal models to test the pathogenicity of
these agents. The blood of 160 patients exposed to living pig tissues
was studied for the presence of PERV. In 135 patients exposure was for
only one hour or a little more. In a few of the remaining patients
exposure was for longer periods, in one case for 460 days. None of the
patients showed evidence of PERV infection, although pig cells
containing retroviral sequences were found even several years after
exposure to the pig tissue42. It is a matter open to
conjecture the extent to which one can take comfort from negative
results in persons exposed for such short period of time, except for a
few cases, and in any event to very few pig cells, as compared with the
years of exposure that would presumably occur in an organ were it
successfully transplanted into a human. Certainly, the elimination from
pigs of all PERV, which represents a continuing concern and hinders the
move to clinical trials, will remain a challenge for years to come.

Advances in Biotechnology and Molecular Genetics

5. The major advances in biotechnology that might favour further
development of xenotransplantation relate to producing transgenic pigs
that express human genes which inhibit rejection. Two break-throughs are
especially important. First, recent studies have led to the cloning of
pigs43, allowing for simple genetic manipulation compared
with the methods currently available. With this procedure, at least in
principle, new genes can easily be introduced into the DNA of the pig
genome during the cloning process, and other genes "knocked
out" so that they would no longer be functional. For instance, the
gene that leads to expression of the "α-gal"
antigen on porcine endothelial cells could be knocked out so that at
least one of the causes of rejection would presumably be reduced.

Second, although still at the experimental level, methods to regulate
the expression of transgenes have been devised44. It may well
be that a certain transgene would be highly desirable at a given moment
after transplantation while it would be undesirable at a different
moment. Therefore, being able to regulate the expression of a transgene
would represent a great advance in the development of
xenotransplantation.

Moving to the clinical phase

6. Because transplanted cells and tissues are not immediately
perfused with recipient blood after transplantation they are not
hyperacutely rejected. Clinical trials using such transplants have
therefore progressed further compared to clinical trials with solid
organ transplants. Porcine pancreatic islets have been transplanted into
a number of patients with diabetes45 and foetal porcine
neural cells have been injected into a significant number of patients
(more than 50) suffering from Parkinson's Disease, Huntington's Disease
or strokes46. Only limited clinical benefit has been reported
to date. A significant number of patients with acute liver failure have
taken part in multicentre studies using pig hepatocytes in artificial
device: (bioartificial liver) with promising initial results47.

There are considerable differences of opinion as to how long a pig
organ should survive in a non-human primate before one proceeds to
clinical trials involving the transplantation of pig organs into humans.
Some suggest that clinical trials on humans could begin only after
routine survival period of ninety days or more have been obtained for
pig organs which are transplanted into nonhuman primates and which must
perform life-supporting functions48. At present, survival
period for this type of xenotransplants vary from a few weeks to about
three months, and three-month survival is certainly not routine49.
Clearly, a significant improvement on current figures must be achieved
before clinical trials using solid organ xenografts are warranted.

However, while survival of pig organs in non-human primates at
present is not sufficiently long to consider transplanting such organs
into humans as a permanent replacement organ, the option of using pig
organs as 'bridge' transplants may well be possible in a shorter time.

PART TWO

ANTHROPOLOGICAL AND ETHICAL ASPECTS

Besides the scientific and technical aspects of xenotransplantation
described in the first part of this document, anthropological and
ethical considerations are also involved. The purpose of this second
part is to explore these considerations, albeit by way of a brief
overview.

Preliminary issues

In addition to the problems raised by every transplant, it seems us
that there are three issues specifically related to xenotransplantation:
1) the acceptabilitv of man's intervening in the order of the creation;
2) the ethical feasibility of using animals to improve the chances for
survival and well-being of human beings; 3) the possible objective and
subjective impact that an organ or tissue of animal origin can have on
the identity of' the human recipient.

Human intervention in the created order

7. To begin with, we would like to deal briefly with a fundamental
question that, generally, is posed by the different religious
traditions, albeit with different accents: this concerns the possibility
itself that man may licitly intervene in the realities that exist in the
universe in general and, more particularly, in those things that concern
animals.

In view of the more specifically theological nature of such a
question, we deem it useful to offer a short summary of the Catholic
position on this question, applying the language and the methods proper
to theological anthropology.

By what right can humans, whom God created as female and male, and
whose full human dignity must be recognized at every stage of life,
intervene in the created order, perhaps even modifying some of its
aspects? What criteria must be adopted and what limitations must be
introduced?

From imagery of the account of creation "in six days"50,
it is evident that God established a hierarchy of values among the
various creatures. Moreover, this hierarchy also emerges from a rational
consideration of the transcendent richness and dignityof the
human person.

Man, created "in the image and likeness of God", isplaced at the centre and at the summit of the created
order, not only because everything that exists is intended for him, but
also because woman and man have the task of co-operating with the
Creator in leading creation to its final perfection. "Be fruitful
and multiply, and fill the earth and subdue it" (Gen 1:28): this is
the mandate that God gives to human beings, "dominion" over
the created order, in his name. In this regard, Pope John Paul II writes
in his encyclical "Laborem Exercens": "Man is the
image of God partly through the mandate received front his Creator to
subdue, to dominate, the earth. In carrying out this mandate, man, every
human being, reflects the very action of the Creator of the
universe"51.

This, therefore, is the deepest meaning of the action of man in
relation to the created universe: certainly not that of arbitrarily
"lording it over" the other creatures, reducing them to
humiliating and destructive slavery in order to satisfy any whim that he
may have, but to guide, through his responsible work, the life of the
creation towards the authentic and integral good of man (the whole man
and every man).

Certain documents of the Second Vatican Council had already affirmed
this truth. In "Lumen Gentium", for example, we read: "Therefore,
by their competence in secular disciplines and by, their activity,
interiorly raised up by grace, they (the laity) must work earnestly in
order that created goods through human labour, technicalskill
and civil culture may serve the utility of all men according to the plan
of the Creator and the light ofhis Word. May these goods be more
suitably distributed among all men and in their own way may they be
conducive to universal progress, in human and Christian liberty"52.
Alsothe decree of the Second Vatican Council on the
apostolate of the laity takes up this idea when it asserts that "this
natural goodness of theirs (of the realities that make up the temporal
order) receives an added dignity from their relation with the human
person, for whose use they have been created"53.

In summary, therefore, there should be a reaffirmation of the right
and duty of man, according to the mandate from his Creator and never
against the natural order established by him, to act within the created
order and on the created order, making use as well, of other creatures,
in order to achieve the final goal of all creation: the glory of God and
the full and definitive bringing about of His Kingdom, through the
promotion of man. The words of St. Irenaeus of Lyons still ring
out with all their truth: "Living man is the glory of God and
man'slife is the vision of God"54.

The Use of Animals for the Good of Man

8. For a theological reflection that will help to formulate an
ethical assessment on the practice of xenotransplantation, we do well to
consider what the intention of the Creator was in bringing animals into
existence. Since they are creatures, animals have their own specific
value which man must recognize and respect. However, God placed them,
together with the other nonhuman creatures, at the service of man, so
that man could achieve his overall development also through them.

It should be noted that this role of "service" rendered to
man by other creatures occurs in different ways according to the
cultural advances of humanity. Limiting ourselves to scientific and
technological progress in the biomedical field, the service of animals
to man represents a totally new application in xenotransplantation,
which therefore, in principle is not in conflict with the order of the
creation. On the contrary, xenotransplantation represents for man a
further opportunity for creative responsibility inmaking
reasonable use of the power that God has given to him.

Furthermore, even if one limits oneself to a purely rational
analysis, without desiring to make use of theological reasoning, one can
reach the same conclusions on a practical level.

A simple look at humanity's long presence on the earth is sufficient
to show an irrefutable fact clearly: it is man who has always directed
the realities of the world, controlling the other living and non-living
beings according to determined purposes. It is moreover in its
relationship with man that the axiological measure (moral value) of
every existing reality is revealed in a universal harmonic and orderly
design that indicates all the fullness of the sense of reality.

In particular, man has always made use of animals for his primary
needs (food, work, clothing, etc.) in a sort of natural
"cooperation" that has constantly marked the different stages
of progress and the development of civilization.

Such a position of "excellence" is a witness to and also
demonstrates the ontological superiority of man over the other beings of
the earth; this superiority is founded on the very nature of the human
person, whose rational and spiritual dimensions place man at the centre
of the universe, so that he may use its existing resources
(including animals) in a wise and responsible manner, seeking the
authentic promotion of every being.

To analyse more deeply the point under discussion, two issues of an
ethical nature must be addressed. First, there is the question of the
use of animals in order to improve man's chances of survival or to
improve his health; the obvious starting point here is the particular
way in which one views the relationship between man and animals55.
Second, there is the question of the acceptability of breaching
the barrier between animal species and the human species.

With regard to the first issue, contemporary thinking includes two
opposing and extreme viewpoints56. There are those who
believe that animals and man have equal dignity and those who believe
that animals are totally at the mercy of man. In the former case, the
use of animals is seen as species-ism or tyranny of man over
animals. Even reducing human suffering could not justify the use of
animals, unless the contrary possibility was also allowed. In the latter
case, man can use animals arbitrarily without being limited by ethical
considerations.

9. From our point of view, supported by the biblical perspective that
asserts, as stated above, that man is created "in the image and
likeness of God" (cf. Gen 1:26-27), we reaffirm that humans
have a unique and higher dignity. However, humans must
also answer to the Creator for the manner in which they treat animals.
As a consequence, the sacrifice of animals can be justified only if
required to achieve an important benefit for man, as is the case with
xenotransplantation of organs or tissues to man, even when this involves
experiments on animals and/or genetically modifying them.

However, even in this case, there is the ethical requirement that in
using animals, man must observe certain conditions: unnecessary animal
suffering must be prevented; criteria of real necessity and
reasonableness must be respected; genetic modifications that could
significantly alter the biodiversity and the balance of the species in
the animal world must be avoided57.

The theological and moral point of view sees no substantial problem
in the utilization of different animal species (nonhuman primates or
nonprimates), but leaves open the question of differing levels of
sensibilities between animals of different species and that of
equilibrium among species and within a species.

The point should also be made that Catholic theology does not have
preclusions, on a religious or ritual basis, in using any animal as a
source of organs or tissues for transplantation to man58. The
question of the acceptability of an animal organ, —once it has
been established that personal identity is not affected by
xenotransplantation, and once all the general ethical requirements of
transplantation have been met, —becomes one on the cultural and
psychological level. Therefore, it may be possible to overcome initial
misgivings by providing the necessary support in an effective manner.

Xenotransplantation and the Identity of the Recipient

10. In addition to considerations of a theological nature, and
perhaps even before these are made, an ethical evaluation of the
practice of xenotransplantation must be measured against current
anthropological findings, especially that branch of philosophical
anthropology that deals with personal identity. Any ethical
appraisal of xenotransplantation must ultimately address the question of
whether the "introduction of a foreign organ into the human body
modifies a person's identity59 and the rich meaning of the
human body?" And if the answer is affirmative, one must ask up to
what point is such modification acceptable.

Certainly, the concept of "personal identity" is replete
with implications and subtleties of meaning, given the different
contributions of philosophy and science60. More concisely, in
keeping with the scope of this document, we can indicate personal
identity as the relation of an individual's unrepeatability and essential
core to his being a person (ontological level) and feeling
that he is a person (psychological level). Thesecharacteristics
are expressed in the person's historical dimension and, in particular,
in his communicative structure, which is always mediated by his
corporeality.

It must be affirmed, then, that personal identity constitutes a good ofthe person, an intrinsic quality of his very being, and thus a
moral value upon which to base the right and duty to promote and defend
the integrityof the personal identity of every
individual.

We can therefore conclude that, in general, the implantation of a
foreign organ into a human body finds an ethical limit in the degree of
change that it may entail in the identity of the person who receives it.

11. Such a modification, as already noted, affects the historical
dimension of the person, and thus the individual's communicative
structure as mediated by his corporeality.

In light of a renewed appreciation of the body and of the symbolic
understanding of it that much of contemporary anthropology offers, it
should be observed that not all organs of the human body are in equal
measure an expression of the unrepeatable identity of the person. There
are some which exclusively perform their specific function; others,
instead, add to their functionality a strong and personal symbolic
element which inevitably depends on the subjectivity of the individual;
and others still, such as the encephalon and the gonads, are
indissolubly linked with the personal identity of the subject because of
their specific function, independently of their symbolic implications.
Therefore one must conclude that whereas the transplantation of these
last can never be morally legitimate, because of the inevitable
objective consequences that they would produce in the recipient or in
his descendants61, those organs which are seen as being
purely functional and those with greater personalized significance
must be assessed, case by case, specifically in relation to the symbolic
meaning which they take on for each individual person62.

12. The questions and issues connected with the defence of the
personal identity of the recipient patient is a central point not only
for philosophical anthropology but also for moral theology , as is
demonstrated by certain official pronouncements of the Magisterium on
xenotransplantation, which see this as one of the fundamental criteria
for the moral legitimacy of xenotransplantation. First Pius XII (Address
to the Italian Association of Corneal Donors, Clinical Ophthalmologists
and Legal Medicine, 14 May 1956), and more recently John Paul II (Address
to the Eighteenth International Congress of the Transplant Society, 29
August. 2000, n. 7), have clearly upheld the moral legitimacy, in
principle, of this therapeutic procedure, on the condition that "the
transplanted organ does not affect the psychological or genetic identity
of the person who receives it" and "that there exists
the proven biological possibility of carrying out such a transplant with
success, without exposing the recipient to excessive risks".

We may observe here that together with the defence of personal
identity, these pronouncements of the Magisterium indicate a second
criterion for the moral legitimacy of xenotransplantation: health
risk. We shall discuss this in greater detail shortly. With
regard to all other issues, from the standpoint of moral theology, the
ethical conditions required for every other kind of transplant apply
also for xenotransplantation".

BIOETHICAL ISSUES

Further investigation and clarification is needed for a wider
bioethical analysis. The ethical evaluation of the practicability of
xenotransplantation, in light of the current situation as summarized in
the first part of this document, requires the consideration of a whole
series of factors, some of which are derived from the general moral
norms valid for all transplants, and others of which are more
specifically related to xenotransplantation64.

The Health Risk

13. As previously stated, one of the fundamental ethical questions
that should be examined when judging the legitimacy of
xenotransplantation is that of the healthrisk involved in
such procedures. This risk is dependent on various factors which cannot
always be predicted or assessed. Before going on, therefore, it may be
useful to recall some general aspects of the ethics of risk.

Risk—understood as an unwanted or damaging future event, the actual
occurrence of which is not certain but possible65—is
defined by means of two characteristics: the level of probability and
the extent of damage. The probability of the occurrence of a certain
damaging event in particular circumstances can be expressed as a risk
percentage or as a statistical frequency. Furthermore, the presence or
absence of certain chance factors of risk can sometimes alter the
probability that a certain event will take place. The extent of the
damage, in contrast, is measured by the effects that the event produces.
Naturally, a very probable risk is easily tolerated if the extent of
damage associated with it is very small; on the contrary, a risk that
causes a high level of damage, however improbable, gives rise to much
greater concern and require greater caution.

It is important to distinguish between a probable event (albeit
with varying degrees of probability) and an event that is only hypothetical;
this latter is an event which is not theoretically impossible but
which is so improbable as to require no change in behaviour or choices.

Together, these two criteria—probability and extent of damage—define
the acceptability of the risk, as reflected by the risk/benefit
ratio. Only when a risk can be concretely assessed it is possible to
apply criteria for evaluating its acceptability.

Lastly, it is necessary to distinguish acceptability from what we can
define as the acceptance ofthe risk, as defined by the
reaction of the individual or of the general public to the existence of
the risk. This is a response that has a significant subjective
component, one which is not always completely thought out and which is
influenced by culture, by the information available and how it is
understood, by the way in which the information itself is communicated,
and by common sensibilities66.

In the absence of data that allow a reliable assessment of such a
risk, greater caution should be used; this does not necessarily mean,
however, that a total "block" should be put on all
experimentation. Indeed, to move from ignorance to knowledge, from the
unknown to the known requires the exploration of new approaches which in
all likelihood, especially during initial experimental stages, will not
be without risks, at least potentially. In this situation, therefore,
the imperative ethical requirement is to proceed by "small
steps" in the acquisition of new knowledge, making use in
experiments of the least possible number of subjects, with careful and
constant monitoring and a readiness at every moment to revise the design
of the experiment on the basis of new data emerging.

It is important to consider the distinction between risk
assessment and risk management. To achieve an ethical
assessment, both elements must be carefully examined.

14. This general discussion of the ethics of risk must now be applied
to the specific case of xenotransplantation.

First of all, we note that there are issues connected with
xenotransplantation, such as the probability of rejection and the
increase in the probability of infection because of immunosuppressive
therapies, about which some degree of knowledge already exists, although
further study is necessary. The data which the scientific community
already possesses, together with new data being gathered, can help to
establish the threshold of risk that must not be crossed if a transplant
operation to be considered morally acceptable.

More complex and uncertain is the assessment and evaluation of risks
connected to one specific aspect of xenotransplantation: the possible
transmission to the recipient of infections arising from the
xenotransplant (zoonoses) by known or unknown pathogenic agents
which are not harmful to the animal but which are possibly dangerous for
man. Such infections could escape detection, with the consequent
possibility of the spread of the infection to those having close
contacts with the patient, leading eventually to its being spread to the
entire population.

Since clinical experience of xenotransplantation is quite limited and
certainly insufficient to provide reliable statistics on the real
probability of occurrences and spread of infections, any decision
concerning clinical development of the new therapy can only be based on
hypothesis. There is, therefore, an ethical requirement to proceed with
the greatest caution.

When the moment for clinical application of xenotransplantation
arrives, it will be necessary to select patients carefully, based on
clear and well-established criteria67, and to monitor the
patient very closely and constantly. One must also contemplate the
possibility of placing the patient in quarantine to prevent the epidemic
spread of an infection. Arrangements for some kind of monitoring of
those having close contacts with patient should also be made.

Moreover, during the experimental phase of clinical trials, patients
should agree not to procreate because of the possible risk of genetic
recombination that could affect the patient's germ cells. Sexual
abstinence would also be necessary to avoid the venereal transmission of
possible viruses.

In the clinical application of xenotransplantation, psychology should
also play an important role. It should address the probable
repercussions that the recipient could undergo in their psyche (e.g
because of the modification of one's "bodily schema") arising
from the acceptance of a foreign organ68, especially when it
comes from an animal69. In the post-transplant stage,
psychology must also provide clinical support for the patient in the
process of integration.

'Trangenesis'

15. The use of organs from engineered animals for
xenotransplantation raises the need for certain reflections on
transgenesis and its ethical implications.

The term "transgenic animal" is used to indicate an animal
whose genetic make-up has been modified by the introduction of a new
gene (or genes). In contrast, the term "knock out" is used to
designate those animals in which a given endogenous gene (or genes) is
no longer expressed. In either case, such animals will express
particular characteristics which will be transmitted to the offspring.

As we have already observed, the possibility of working out such
genetic modifications, using genes of human origin as well, is morally
acceptable when done in respect for the animal and for biodiversity, and
with a view to bringing significant benefits to man himself. Therefore,
while recognizing that transgenesis does not compromise the
overall genetic identity of the mutated animal or its species, and
reaffirming man's responsibility towards the created order and towards
the pursuit of improving health by means of certain types of genetic
manipulation, we will now enumerate some fundamental ethical conditions
which must be respected:

1. Concern for the well-being of genetically modified animals should
be guaranteed so that the effect of the transgene's expression,
possible modification of the anatomical, physiological and/or
behavioural aspects of the animal may be assessed, all the while
limiting the levels of stress and pain, suffering and anxiety
experienced by the animal;

2. The effects on the offspring and possible repercussions for the
environment should be considered;

3. Such animals should be kept under tight control and should not be
released into the general environment;

4. The number of animals used in experiments should be kept to a bare
minimum;

5. The removal of organs and/or tissues must take place during a
single surgical operation;

6. Every experimental protocol on animals must be evaluated by a
competent ethics committee.

Informed Consent

16. In the ethical discussion on xenotransplantation, the subject of
informed consent also deserves special attention70.

Given the animal source of the organs which will be transplanted,
this issue concerns only the recipient and, secondly, his relatives. At
the outset the recipient should be given every information regarding his
pathology and its prognosis, the xenotransplant operation and subsequent
therapy, and the probability of success and the risks of rejection.
Special attention should be paid to making sure that the patient is
informed about the real and hypothetical risks of zoonoses, in light of
current data, and about the precautions to be adopted in the case of
infection (in particular the possible need for quarantine, which
involves avoiding physical contact with others while the risk of
contagion is present). The patient must also be informed about the need
to remain under medical supervision for the rest of his life, so that
thenecessary constant monitoring following the transplant may be
carried out. In addition, adequate information on possible alternative
therapies to xenotransplant therapy should not be withheld.

This informed consent on the partof the patient should be
understood as personal. For this reason, minors and those unable
to give valid consent are to be excluded from the experimental phase.

However, if a patient incapable of giving valid consent should find
himself in a previously unforeseen situation where there is danger of
imminent death, recourse may be made to a legal representative (e.g. in
the hypothetical case of a life-saving xenotransplant as a
temporary solution for a patient in a coma), provided that the medical
procedures to be used offers a reasonable hope of benefit for the
patient.

The patient's relatives should also be informed about what the
transplant could entail regarding their contact with the patient and
about the possible risks of contagion should an infection, as mentioned
above, set in. In a strict sense, however, consent cannot be requested
from them, since it is the patient who is ultimately responsible for the
choices concerning his own health.

Allocation of Health Care Resources

17. Xenotransplantation certainly represents a form of possible
treatment requiring a great outlay of both health care resources and
economic resource71. For this reason, some people have
expressed doubts about its ethical validity; given the large amounts of
resources that it would take away from the other forms of therapeutic
treatment and from other area of research, they consider both the
uncertainty about its success and the risk entailed to be excessive.
Faced with these doubts, it is important to remember that, even taken
into due consideration the costs-benefits balance, the huge amount of
health care resources used in this case is justified by the urgent need
to try to save the lives of so many patients who would otherwise have no
chance of survival.

It should also be added that as long as xenotransplantation on man
remains at an experimental stage it should not be subject to the
criteria applied to treatment in strict sense; rather it should be
evaluated according to the criteria used for trials. Therefore, the
foreseeable collective benefits that it may accrue in the future should
also be taken into account. We do well to recognize here that the
research into xenotransplantation which has taken place so far has also
brought about greater medical knowledge in the area of
allotransplantation.

Patentability and Xenotransplantation

18. Research on xenotransplantation has hitherto in large measure
been carried out largely by private pharmaceutical companies which have
committed substantial economic resources to this endeavour; they have
also been providing financing to public institutions for the purpose of
obtaining better therapeutic results. It is therefore reasonable for
them to expect an economic return on the investment made; one of the
possible ways to do this is by acquiring patents.

From a formal point of view, there is no technical or legal obstacle
standing in the way of the patenting genetically engineered animal
organs intended for transplants72. It should be emphasised
however that the norms drawn up by the European Community to regulate
this matter could not, at the time they were being drafted, take into
account the use of such organs for transplant from animal to man, since
this therapeutic procedure had not yet been accomplished in clinical
practice. We therefore stress that, given the extraordinary financial
commitment that has been made, now is the time to reconsider—or rather
to be more precise about it—the specific norms that apply.

We are aware of the broad debate underway on the basic question of
whether the possibility itself of patenting living beings (even though
genetically modified) or parts of them, especially when they contain
genetic elements derived from humans (as is the case with animal organs
genetically engineered for xenotransplantation into man), is ethically
acceptable. We are also aware that there is a difference between a
"discovery" (which cannot be patented) and an
"invention" (which can be patented). Although it is our view
that the transgenic animal as such—and all the more when they are used
for transplantation into man—should be considered "nonpatentable",
we nonetheless believe that it is not the purpose of present document to
address this complex question directly.

Here, we shall limit ourselves to emphasising that, whatever answer
may be given to this basic question, it is always necessary—as a bare
minimum—to guarantee respect for the fundamental right of every person
to equitable access to the health care they may be needed, without
discrimination and without being impeded by excessive costs. This
applies above all else to accessibility to treatment. This objective—in
the hypothetical case of patents connected with xenotransplantation, a
procedure which should be viewed from a therapeutic standpoint—can be
reached by making appropriate legal requirements apply (for example, the
introduction of compulsory licences), thus allowing
"production" at accessible prices73 which would
hopefully be controlled by a supranational body specifically set up for
this purpose.

Practical Guidelines

19. Bearing in mind all that has been said above, we can now present
a practical approach which will guide the path of research and
development in the area of xenotransplantation as applied to man.

Regarding the xenotransplantation of solid organs, it is of course
necessary that pre-clinical experiments (from animal to animal) should
continue for as long as scientists should require and until repeatable
positive results are obtained, results which are considered sufficient
to allow trials on man to begin.

When the moment arrives, it will be ethically correct, respecting the
rules of informed consent indicated above, to involve initially only a
restricted group of patients, patients who cannot be chosen—in the
given circumstances—for allotransplantation (whether because of
waiting lists or individual counter-indications), and for whom no better
alternative treatment is available.

A commensurate moral imperative is that of ensuring careful and
detailed monitoring of' the individuals who receive a xenograft, a
situation which could foreseeably continue for the rest of the patient's
life, watching for any sign of possible infection caused by known and
unknown pathogenic agents.

In addition, every experimental clinical trial should be carried out
in highly specialised centres with proven experience in pre-clinical
pig-to-primate models; these centres should be authorised and supervised
by the competent health care authorities.

The results thus obtained, if unequivocally positive, would
constitute the basis for extending the practice of xenotransplantation,
making it an accepted surgical therapy.

20. The questions and issues related to xenotransplantation have
implications of a very wide social character. There is thus an ethical
need to acquire correct information on the topics of greatest public
interest with regard to the potential benefits and risks. This
information should be communicated to as large a segment of the public
as possible. Moreover, by means of debates and public discussions in
small and large groups, society itself, through its representatives,
should help to identify the conditions under which they would find it
acceptable to invest resources and hope in this new therapeutic
approach, in light of the scientific uncertainties which are still
present and the urgent need to increase the availability of organs which
can be transplanted.

A serious ethical commitment on the part of scientists should not
neglect to explore therapeutic paths which may represent alternatives to
xenotransplantation, such as seem to be promised by many recent
discoveries in the field of genetics, as in a longer period the
therapeutic use of adult stem cells.

21. With respect to the specific fields of health-related policies
and legislation on matters of xenotransplantation, it is our heartfelt
hope that the considerations offered in the present document will
provide a useful point of reference for all those who—at an
international, national, regional and local level—are responsible for
leading society. Many countries74 have already developed
guidelines to regulate this complex sector, offering helpful operational
directives.

On our part, we do not believe that this document should enter into
procedural political-legislative matters. We therefore limit ourselves
to emphasizing the importance and desirability that a substantial
convergence of international legislation in this area should be achieved
as soon as possible, by means of a genuine coordination at the different
levels. On the one hand such legislation must provide rules for the
continuation of scientific research, guaranteeing its validity and
safety; on the other hand it must watch over the health of the citizens
involved and the potential risks (especially infective) connected with
xenotransplantation. Furthermore it must offer criteria for organizing
the necessary information campaigns aimed at the entire population.

We conclude this document with the sincere hope that the effort made
on this study by those who have participated in it—scientists,
jurists, theologians and bioethicists—will represent a concrete
contribution to the development of the discussion on the important theme
of xenotransplantation. May it also be seen as a further expression of
the close attention which the Catholic Church pays on problems related
to human disease and suffering.

Juan DE DIOS VIAL CORREAPresident

Elio SGRECCIAVice-President

(Published as supplement to "L'Osservatore Romano", 26
September 2001)

NOTES

1 Cf. Evans R., Orians C., Ascher N., The potential supply of
organ donors; an assessment of the efficacy of organ procurement efforts
in the United States. JAMA 1992; 267:239-46.

48 Cf. Cooper D.K.C., Keogh A.M., Brink J., et al., Report of the
xenotransplantation advisory committee of the international society for
heart and lung transplantation. The present status of
xenotransplantation and its potential role in the treatment of endstage
cardiac and pulmonary disease. J. Heart Lung Transpl. 2000,
19:1125-1165.

50 The reference is made to the narrative scheme, of a
theological-liturgical nature, used in Gn 1:1-31; for a fuller
understanding of the biblical anthropological context, from a
protological point of view, the second account of creation, in Gn
2:1-25, must also be taken into consideration.

61 We do well to specify that, while the encephalon is related to the
personal identity of the subject insofar as it is the organ representing
the "principal seat of psychological consciousness", and the
"deposit" of existential memory, the gonads are likewise
related, insofar as they are organs charged with gametogenesis (the
production of gametes); they represent, in a manner of speaking, the
"transmitter"—by means of procreation—of the subject's
personal identity (genetic patrimony) to offspring. For this reason,
while an hypothetical encephalon transplant can in no case be considered
morally licit, neither can an eventual gonad transplant—if performed
for the purpose of supplying the gametogenetic function—be morally
acceptable. Different, however, is the case of a gonad transplant
performed exclusively for hormonogenetic purposes (that is, to restore a
sufficient hormonal function); once the integrity of the subject's
personal identity has been ensured, and once the disassociation with
procreation has been established, there would be no particular moral
reservations. In this regard, see M.P. Faggioni, Iltrapianto
di gonadi. Storia e attualità, Med. Mor., 1998, 48, 15-46.

66 An overview of social reactions to different aspects of
xenotransplantation: Appel J.Z., Alwayn I.P., Cooper D.K., Xenotransplantation:
The Challenge to Current Psychological Attitudes, Prog Transplant
2000, 10:217-225.

74 To give a few examples of some important organizations that have
drafted guidelines in this area, we list the following: the Council of
Europe, the Health Council of the Netherlands, the Swedish Committee on
Xenotransplantation, the Spanish Xenotransplantation Sub-committee, the
Argentine National Commission on Xenotransplantation, the U.S.
Department of Health and Human Services Committee on Xenotransplantation,
the United Kingdom Xenotransplantation Interim Regulatory Authority, and
the Italian Xenotransplantation Commission. In France, the ethical
aspects are currently being examined by the French National Ethics
Committee and applications for clinical trials will need the approval of
the newly formed Agency for the Security of Health Products and of the
Ministry of Health. In Germany, the German Medical Council has
established a committee to prepare guidelines on xenotransplantation. In
Canada 'Health Canada' has the authority to regulate xenotransplantation
as a new technology.

Taken from:
L'Osservatore Romano
Weekly Edition in English
28 November 2001, special insert

L'Osservatore Romano is the newspaper of the Holy See.
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